Allogeneic Hematopoietic Stem Cell Transplantation After Prior Lung Transplantation for Hereditary Pulmonary Alveolar Proteinosis: A Case Report

Pulmonary alveolar proteinosis (PAP) is a rare, diffuse lung disorder characterized by surfactant accumulation in the small airways due to defective clearance by alveolar macrophages, resulting in impaired gas exchange. Whole lung lavage is the current standard of care treatment for PAP. Lung transplantation is an accepted treatment option when whole lung lavage or other experimental treatment options are ineffective, or in case of extensive pulmonary fibrosis secondary to PAP. A disadvantage of lung transplantation is recurrence of PAP in the transplanted lungs, especially in hereditary PAP. The hereditary form of PAP is an ultra-rare condition caused by genetic mutations in genes encoding for the granulocyte macrophage-colony stimulating factor (GM-CSF) receptor, and intrinsically affects bone marrow derived-monocytes, which differentiate into macrophages in the lung. Consequently, these macrophages typically display disrupted GM-CSF receptor-signaling, causing defective surfactant clearance. Bone marrow/hematopoietic stem cell transplantation may potentially reverse the lung disease in hereditary PAP. In patients with hereditary PAP undergoing lung transplantation, post-lung transplant recurrence of PAP may theoretically be averted by subsequent hematopoietic stem cell transplantation, which results in a graft-versus-disease (PAP) effect, and thus could improve long-term outcome. We describe the successful long-term post-transplant outcome of a unique case of end-stage respiratory failure due to hereditary PAP-induced pulmonary fibrosis, successfully treated by bilateral lung transplantation and subsequent allogeneic hematopoietic stem cell transplantation. Our report supports treatment with serial lung and hematopoietic stem cell transplantation to improve quality of life and prolong survival, without PAP recurrence, in selected patients with end-stage hereditary PAP

The role of HLA-DP mismatches and donor specific HLA-DP antibodies in kidney transplantation: a case series.

BACKGROUND: The impact of HLA-DP mismatches on renal allograft outcome is still poorly understood and is suggested to be less than that of the other HLA loci. The common association of HLA-DP donor-specific antibodies (DSA) with other DSA obviates the evaluation of the actual effect of HLA-DP DSA. METHODS: From a large multicenter data collection, we retrospectively evaluated the significance of HLA-DP DSA on transplant outcome and the immunogenicity of HLA-DP eplet mismatches with respect to the induction of HLA-DP DSA. Furthermore, we evaluated the association between the MFI of HLA-DP antibodies detected in Luminex assays and the outcome of flowcytometric/complement-dependent cytotoxicity (CDC) crossmatches. RESULTS: In patients with isolated pretransplant HLA-DP antibodies (N = 13), 6 experienced antibody-mediated rejection (AMR) and 3 patients lost their graft. In HLAMatchmaker analysis of HLA-DP mismatches (N = 72), HLA-DP DSA developed after cessation of immunosuppression in all cases with 84DEAV (N = 14), in 86% of cases with 85GPM (N = 6/7), in 50% of cases with 56E (N = 6/12) and in 40% of cases with 56A mismatch (N = 2/5). Correlation analysis between isolated HLA-DP DSA MFI and crossmatches (N = 90) showed negative crossmatch results with HLA-DP DSA MFI <2000 (N = 14). Below an MFI of 10,000 CDC crossmatches were also negative (N = 33). Above these MFI values both positive (N = 35) and negative (N = 16) crossmatch results were generated. CONCLUSIONS: Isolated HLA-DP DSA are rare, yet constitute a significant risk for AMR. We identified high-risk eplet mismatches that can lead to HLA-DP DSA formation. We therefore recommend HLA-DP typing to perform HLA-DP DSA analysis before transplantation. HLA-DP DSA with high MFI were not always correlated with positive crossmatch results.status: Published onlin

Eplet Mismatch Load and De Novo

BACKGROUND: In kidney transplantation, evaluating mismatches of HLA eplets—small patches of surface-exposed amino acids of the HLA molecule—instead of antigen mismatches might offer a better approach to assessing donor-recipient HLA incompatibility and improve risk assessment and prediction of transplant outcomes. METHODS: To evaluate the effect of number of eplet mismatches (mismatch load) on de novo formation of donor-specific HLA antibodies (DSAs) and transplant outcomes, we conducted a cohort study that included consecutive adult kidney recipients transplanted at a single center from March 2004 to February 2013. We performed retrospective high-resolution genotyping of HLA loci of 926 transplant pairs and used the HLAMatchmaker computer algorithm to count HLA eplet mismatches. RESULTS: De novo DSAs occurred in 43 (4.6%) patients. Multivariable analysis showed a significant independent association between antibody-verified eplet mismatch load and de novo DSA occurrence and graft failure, mainly explained by DQ antibody-verified eplet effects. The association with DQ antibody-verified eplet mismatches was linear, without a safe threshold at which de novo DSA did not occur. Odds for T cell– or antibody-mediated rejection increased by 5% and 12%, respectively, per antibody-verified DQ eplet mismatch. CONCLUSIONS: Eplet mismatches in HLA-DQ confer substantial risk for de novo DSA formation, graft rejection, and graft failure after kidney transplantation. Mismatches in other loci seem to have less effect. The results suggest that antibody-verified HLA-DQ eplet mismatch load could be used to guide personalized post-transplant immunosuppression. Adoption of molecular matching for DQA(1) and DQB(1) alleles could also help to minimize de novo DSA formation and potentially improve transplant outcomes